Abstracts from 5 August 2022

Journal of Psychophysiology     Volume 175, May 2022, Pages 61-70
Blunted short-term autonomic cardiovascular reactivity to orthostatic and clinostatic challenges in fibromyalgia as an indicator of the severity of chronic pain
Author links open overlay panelAna M.Contreras-MerinoaDmitry M.DavydovbcCarmen M.Galvez-SánchezaGustavo A.Reyes del Pasoa 
https://doi.org/10.1016/j.ijpsycho.2022.03.001
Highlights
Fibromyalgia (FM) has been related to autonomic cardiovascular disturbances.
Short-term cardiovascular responses to gravitational stress were assessed in FM.
FM sufferers showed blunted cardiovascular responses in the first 30 s.
Cardiovascular reactivity correlated to pain, quality of life and affect in FM.
High temporal resolution measures are encouraged in postural stress research in FM.
Abstract
Fibromyalgia is a long-term pain disorder that has been related to autonomic dysfunctions and reduced cardiovascular reactivity. We aimed to assess the dynamic short-term cardiovascular responses to postural changes in fibromyalgia. Thirty-eight women with fibromyalgia and thirty-six healthy women underwent the “Chronic Pain Autonomic Stress Test”. Electrocardiogram, blood pressure and impedance cardiography were continuously recorded during active standing and lying down. Second-by-second values were derived over the first 30 s of each posture. Lower reactivity during the beginning of each position was observed in fibromyalgia sufferers compared to healthy women, with smaller responses seen during stand up in heart rate, blood pressure, cardiac output, total peripheral resistance, and pre-ejection period, and smaller changes during lying down in heart rate, cardiac output and total peripheral resistance. The magnitude of the autonomic adjustments to postural changes was inversely associated with the severity of clinical pain. These findings indicate an early impaired autonomic cardiovascular response to orthostatic and clinostatic challenges in fibromyalgia, suggesting less autonomic flexibility and adaptability to situational demands and challenges. Short-term second-by-second cardiovascular measures may be useful in the clinical assessment of fibromyalgia.
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Front Cell Neuroscience . 2022 May 9;16:888232.  doi: 10.3389/fncel.2022.888232. eCollection 2022.
The Pathobiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Case for Neuroglial FailureHerbert Renz-Polster 1, Marie-Eve Tremblay 2 3 4 5 6 7, Dorothee Bienzle 8, Joachim E Fischer 1
PMID: 35614970  PMCID: PMC9124899    DOI: 10.3389/fncel.2022.888232
AbstractAlthough myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has a specific and distinctive profile of clinical features, the disease remains an enigma because causal explanation of the pathobiological matrix is lacking. Several potential disease mechanisms have been identified, including immune abnormalities, inflammatory activation, mitochondrial alterations, endothelial and muscular disturbances, cardiovascular anomalies, and dysfunction of the peripheral and central nervous systems. Yet, it remains unclear whether and how these pathways may be related and orchestrated. Here we explore the hypothesis that a common denominator of the pathobiological processes in ME/CFS may be central nervous system dysfunction due to impaired or pathologically reactive neuroglia (astrocytes, microglia and oligodendrocytes). We will test this hypothesis by reviewing, in reference to the current literature, the two most salient and widely accepted features of ME/CFS, and by investigating how these might be linked to dysfunctional neuroglia. From this review we conclude that the multifaceted pathobiology of ME/CFS may be attributable in a unifying manner to neuroglial dysfunction. Because the two key features - post exertional malaise and decreased cerebral blood flow - are also recognized in a subset of patients with post-acute sequelae COVID, we suggest that our findings may also be pertinent to this entity.

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Medscape Medical News
Study: Long COVID Patients Have Immune System DifferencesKara Grant
August 11, 2022
Using immune profiling, a small but intense study found that people with long COVID have increased antibody responses to other non-COVID viruses, like Epstein-Barr Virus (EBV), as well as significantly lowered cortisol levels compared with people without long COVID.
The study — which is still a preprint, meaning it has yet to be peer-reviewed — looked at 215 people from Mount Sinai Hospital in New York City and Yale New Haven Hospital in Connecticut.
The 215 study participants were placed into four groups:

• healthy individuals who haven't been previously infected with COVID-19
• healthy, unvaccinated people who have had COVID
• healthy, vaccinated people who have had COVID with no lingering symptoms
• individuals who have had persistent symptoms following acute COVID infection

According to Yale immunology professor Akiko Iwasaki, PhD, and co-authors, an unexpected development in the group's research revealed that subsets of long COVID patients had antibody reactivity against non-COVID viruses, particularly Epstein-Barr Virus (EBV), a member of the herpes virus family.
The presence of EBV has been previously reported during severe COVID-19 infection in hospitalized patients. But the elevated immune responses to EBV found among patients in this study indicate a recent reactivation of this particular virus may be a common feature of long COVID.
The profiling conducted in the study found that the reactivation of EBV is not just incidental following a COVID-19 infection. In fact, the researchers write that these kinds of non-COVID viral pathogens "may alternatively mediate, aggravate, or exploit the persistent changes” in people with long COVID.
It's unclear, however, whether EBV reactivation may predispose those with long COVID to the development or worsening of autoimmune diseases, which has been reported among people with multiple sclerosis.
Additionally, one of the most striking findings was that participants with long COVID had significant decreases in levels of cortisol, the body's main stress hormone.
"Prior reports have associated low cortisol levels during the early phase of COVID-19 in patients that develop respiratory long COVID symptoms,” Iwasaki and colleagues write in the study. "Thus, our current finding of persistently decreased cortisol production in participants with long COVID more than a year following acute infection warrants expanded investigation.”
The authors note several important limitations to this study, primarily its small participant pool of 215 persons. While the individuals who participated were extensively immune profiled, the limited number hinders the study's ability to be broadly applicable to the general population.
 
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medRxiv  . 2022 Jan 11;2021.06.14.21258895.  doi: 10.1101/2021.06.14.21258895. Preprint
Evidence for Peroxisomal Dysfunction and Dysregulation of the CDP-Choline Pathway in Myalgic Encephalomyelitis/Chronic Fatigue SyndromeXiaoyu Che 1 2, Christopher R Brydges 3, Yuanzhi Yu 2, Adam Price 1, Shreyas Joshi 1, Ayan Roy 1, Bohyun Lee 1, Dinesh K Barupal 4, Aaron Cheng 1, Dana March Palmer 5, Susan Levine 6, Daniel L Peterson 7, Suzanne D Vernon 8, Lucinda Bateman 8, Mady Hornig 5, Jose G Montoya 9, Anthony L Komaroff 10, Oliver Fiehn 3, W Ian Lipkin 1
PMID: 35043127  PMCID: PMC8764736  DOI: 10.1101/2021.06.14.21258895
Update in·       Metabolomic Evidence for Peroxisomal Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.
Che X, Brydges CR, Yu Y, Price A, Joshi S, Roy A, Lee B, Barupal DK, Cheng A, Palmer DM, Levine S, Peterson DL, Vernon SD, Bateman L, Hornig M, Montoya JG, Komaroff AL, Fiehn O, Lipkin WI.Int J Mol Sci. 2022 Jul 18;23(14):7906. doi: 10.3390/ijms23147906.PMID: 35887252 
AbstractBackground: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic and debilitating disease that is characterized by unexplained physical fatigue unrelieved by rest. Symptoms also include cognitive and sensory dysfunction, sleeping disturbances, orthostatic intolerance, and gastrointestinal problems. A syndrome clinically similar to ME/CFS has been reported following well-documented infections with the coronaviruses SARS-CoV and MERS-CoV. At least 10% of COVID-19 survivors develop post acute sequelae of SARS-CoV-2 infection (PASC). Although many individuals with PASC have evidence of structural organ damage, a subset have symptoms consistent with ME/CFS including fatigue, post exertional malaise, cognitive dysfunction, gastrointestinal disturbances, and postural orthostatic intolerance. These common features in ME/CFS and PASC suggest that insights into the pathogenesis of either may enrich our understanding of both syndromes, and could expedite the development of strategies for identifying those at risk and interventions that prevent or mitigate disease.
Methods: Using regression, Bayesian and enrichment analyses, we conducted targeted and untargeted metabolomic analysis of 888 metabolic analytes in plasma samples of 106 ME/CFS cases and 91 frequency-matched healthy controls.
Results: In ME/CFS cases, regression, Bayesian and enrichment analyses revealed evidence of peroxisomal dysfunction with decreased levels of plasmalogens. Other findings included decreased levels of several membrane lipids, including phosphatidylcholines and sphingomyelins, that may indicate dysregulation of the cytidine-5’-diphosphocholine pathway. Enrichment analyses revealed decreased levels of choline, ceramides and carnitines, and increased levels of long chain triglycerides (TG) and hydroxy-eicosapentaenoic acid. Elevated levels of dicarboxylic acids were consistent with abnormalities in the tricarboxylic acid cycle. Using machine learning algorithms with selected metabolites as predictors, we were able to differentiate female ME/CFS cases from female controls (highest AUC=0.794) and ME/CFS cases without self-reported irritable bowel syndrome (sr-IBS) from controls without sr-IBS (highest AUC=0.873).
Conclusion: Our findings are consistent with earlier ME/CFS work indicating compromised energy metabolism and redox imbalance, and highlight new abnormalities that may provide insights into the pathogenesis of ME/CFS.
One sentence summary: Plasma levels of plasmalogens are decreased in patients with myalgic encephalomyelitis/chronic fatigue syndrome suggesting peroxisome dysfunction.

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Neurology  May 19, 2022
Comparison of Amitriptyline and US Food and Drug Administration–Approved Treatments for FibromyalgiaA Systematic Review and Network Meta-analysisHussein M. Farag, PharmD, MSc, PhD1; Ismaeel Yunusa, PharmD, PhD1,2; Hardik Goswami, BPharm, MSc, PhD1,3; et alIhtisham Sultan, PharmD1,4; Joanne A. Doucette, MSc, MSLIS1; Tewodros Eguale, MD, PhD1,5
JAMA Netw Open. 2022;5(5):e2212939. doi:10.1001/jamanetworkopen.2022.12939
Key Points
Question  What pharmacological treatments for adults with fibromyalgia are associated with the highest efficacy and acceptability?
Findings  In this systematic review and network meta-analysis of 36 randomized clinical trials (11 930 patients with fibromyalgia), duloxetine (120 mg) was associated with higher efficacy in treating pain and depression, while amitriptyline was associated with higher efficacy and acceptability in improving sleep, fatigue, and health-related quality of life outcomes.
Meaning  These findings suggest that with the heterogeneity of fibromyalgia symptoms, pharmacological treatments should be tailored to individual symptoms, including pain, sleep problems, depressed mood, fatigue, and health-related quality of life.
Abstract
Importance  Amitriptyline is an established medication used off-label for the treatment of fibromyalgia, but pregabalin, duloxetine, and milnacipran are the only pharmacological agents approved by the US Food and Drug Administration (FDA) to treat fibromyalgia.
Objective  To investigate the comparative effectiveness and acceptability associated with pharmacological treatment options for fibromyalgia.
Data Sources  Searches of PubMed/MEDLINE, Cochrane Library, Embase, and Clinicaltrials.gov were conducted on November 20, 2018, and updated on July 29, 2020.
Study Selection  Randomized clinical trials (RCTs) comparing amitriptyline or any FDA-approved doses of investigated drugs.
Data Extraction and Synthesis  This study follows the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline. Four independent reviewers extracted data using a standardized data extraction sheet and assessed quality of RCTs. A random-effects bayesian network meta-analysis (NMA) was conducted. Data were analyzed from August 2020 to January 2021.
Main Outcomes and Measures  Comparative effectiveness and acceptability (defined as discontinuation of treatment owing to adverse drug reactions) associated with amitriptyline (off-label), pregabalin, duloxetine, and milnacipran (on-label) in reducing fibromyalgia symptoms. The following doses were compared: 60-mg and 120-mg duloxetine; 150-mg, 300-mg, 450-mg, and 600-mg pregabalin; 100-mg and 200-mg milnacipran; and amitriptyline. Effect sizes are reported as standardized mean differences (SMDs) for continuous outcomes and odds ratios (ORs) for dichotomous outcomes with 95% credible intervals (95% CrIs). Findings were considered statistically significant when the 95% CrI did not include the null value (0 for SMD and 1 for OR). Relative treatment ranking using the surface under the cumulative ranking curve (SUCRA) was also evaluated.
Results  A total of 36 studies (11 930 patients) were included. The mean (SD) age of patients was 48.4 (10.4) years, and 11 261 patients (94.4%) were women. Compared with placebo, amitriptyline was associated with reduced sleep disturbances (SMD, −0.97; 95% CrI, −1.10 to −0.83), fatigue (SMD, −0.64; 95% CrI, −0.75 to −0.53), and improved quality of life (SMD, −0.80; 95% CrI, −0.94 to −0.65). Duloxetine 120 mg was associated with the highest improvement in pain (SMD, −0.33; 95% CrI, −0.36 to −0.30) and depression (SMD, −0.25; 95% CrI, −0.32 to −0.17) vs placebo. All treatments were associated with inferior acceptability (higher dropout rate) than placebo, except amitriptyline (OR, 0.78; 95% CrI, 0.31 to 1.66). According to the SUCRA-based relative ranking of treatments, duloxetine 120 mg was associated with higher efficacy for treating pain and depression, while amitriptyline was associated with higher efficacy for improving sleep, fatigue, and overall quality of life.
Conclusions and Relevance  These findings suggest that clinicians should consider how treatments could be tailored to individual symptoms, weighing the benefits and acceptability, when prescribing medications to patients with fibromyalgia.

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Published: 22 March 2022
Endothelial dysfunction and altered endothelial biomarkers in patients with post-COVID-19 syndrome and chronic fatigue syndrome (ME/CFS)Milan Haffke, Helma Freitag, Gordon Rudolf, Martina Seifert, Wolfram Doehner, Nadja Scherbakov, Leif Hanitsch, Kirsten Wittke, Sandra Bauer, Frank Konietschke, Friedemann Paul, Judith Bellmann-Strobl, Claudia Kedor, Carmen Scheibenbogen & Franziska Sotzny 
Journal of Translational Medicine volume 20, Article number: 138 (2022)  
AbstractBackgroundFatigue, exertion intolerance and post-exertional malaise are among the most frequent symptoms of Post-COVID Syndrome (PCS), with a subset of patients fulfilling criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). As SARS-CoV-2 infects endothelial cells, causing endotheliitis and damaging the endothelium, we investigated endothelial dysfunction (ED) and endothelial biomarkers in patients with PCS.
MethodsWe studied the endothelial function in 30 PCS patients with persistent fatigue and exertion intolerance as well as in 15 age- and sex matched seronegative healthy controls (HCs). 14 patients fulfilled the diagnostic criteria for ME/CFS. The other patients were considered to have PCS. Peripheral endothelial function was assessed by the reactive hyperaemia index (RHI) using peripheral arterial tonometry (PAT) in patients and HCs. In a larger cohort of patients and HCs, including post-COVID reconvalescents (PCHCs), Endothelin-1 (ET-1), Angiopoietin-2 (Ang-2), Endocan (ESM-1), IL-8, Angiotensin-Converting Enzyme (ACE) and ACE2 were analysed as endothelial biomarkers.
ResultsFive of the 14 post-COVID ME/CFS patients and five of the 16 PCS patients showed ED defined by a diminished RHI (< 1.67), but none of HCs exhibited this finding. A paradoxical positive correlation of RHI with age, blood pressure and BMI was found in PCS but not ME/CFS patients. The ET-1 concentration was significantly elevated in both ME/CFS and PCS patients compared to HCs and PCHCs. The serum Ang-2 concentration was lower in both PCS patients and PCHCs compared to HCs.
ConclusionA subset of PCS patients display evidence for ED shown by a diminished RHI and altered endothelial biomarkers. Different associations of the RHI with clinical parameters as well as varying biomarker profiles may suggest distinct pathomechanisms among patient subgroups.

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2022 Jun; 13(3): 698–711.Published online 2022 Jun 1. doi: 10.14336/AD.2021.0824
PMCID: PMC9116917  PMID: 35656104   Ageing and Disease
The Role of Kynurenine Pathway and NAD+ Metabolism in Myalgic Encephalomyelitis/Chronic Fatigue SyndromeMona Dehhaghi, 1 , 2 Hamed Kazemi Shariat Panahi, 1 Bahar Kavyani, 1 Benjamin Heng, 1 , 2 Vanessa Tan, 1 , 2 Nady Braidy, 3 and Gilles J. Guillemin 1 , 
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a serious, complex, and highly debilitating long-term illness. People with ME/CFS are typically unable to carry out their routine activities. Key hallmarks of the disease are neurological and gastrointestinal impairments accompanied by pervasive malaise that is exacerbated after physical and/or mental activity. Currently, there is no validated cure of biomarker signature for this illness. Impaired tryptophan (TRYP) metabolism is thought to play significant role in the pathobiology of ME/CFS. TRYP is an important precursor for serotonin and the essential pyridine nucleotide nicotinamide adenine dinucleotide (NAD+). TRYP has been associated with the development of some parts of the brain responsible for behavioural functions. The main catabolic route for TRYP is the kynurenine pathway (KP). The KP produces NAD+ and several neuroactive metabolites with neuroprotective (i.e., kynurenic acid (KYNA)) and neurotoxic (i.e., quinolinic acid (QUIN)) activities. Hyperactivation of the KP, whether compensatory or a driving mechanism of degeneration can limit the availability of NAD+ and exacerbate the symptoms of ME/CFS. This review discusses the potential association of altered KP metabolism in ME/CFS. The review also evaluates the role of the patient’s gut microbiota on TRYP availability and KP activation. We propose that strategies aimed at raising the levels of NAD+ (e.g., using nicotinamide mononucleotide and nicotinamide riboside) may be a promising intervention to overcome symptoms of fatigue and to improve the quality of life in patients with ME/CFS. Future clinical trials should further assess the potential benefits of NAD+ supplements for reducing some of the clinical features of ME/CFS.
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Queensland researchers find overlap in pathology of long COVID and chronic fatigue syndromeABC Gold Coast  / By Heidi Sheehan   Posted Thu 11 Aug 2022 at 10:37amThursday 11 Aug 2022 at 10:37am, updated Thu 11 Aug 2022 at 2:52pm
Researchers say they have found a link in the pathology between long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). 
Key points:

• Griffith University researchers say their findings could help to treat those suffering from long COVID
• A woman with chronic fatigue syndrome says she suffered a relapse in symptoms after contracting COVID earlier this year
• AMA Queensland says the findings should be independently verified and that more funding for such research should be made available

The work is being carried out by Professor Sonya Marshall-Gradisnik and the team at Griffith University's National Centre for Neuroimmunology and Emerging Diseases (NCNED).
"It is the first of its kind in the world to actually biologically identify the overlap in the dysfunction with long COVID and ME/CFS patients," she said.
Dr Marshall-Gradisnik said damaged receptors, like a dysfunctional lock and key, do not allow enough calcium in.
"The receptors are located on every cell in the body," she said.
"These ion channels, or the lock and the key that tries to open the door — when we look at ME/CFS patients, that's been significantly impaired.
"When we looked at the same receptor [in long COVID patients], we're now reporting the same change."
The findings will be published in the Journal of Molecular Medicine.
 
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Brain Behav Immun Health. 2022 Oct; 24: 100485.
Published online 2022 Jul 3. doi: 10.1016/j.bbih.2022.100485  PMCID: PMC9250701 PMID: 35814187
Safety and efficacy of low dose naltrexone in a long covid cohort; an interventional pre-post study
Brendan O'Kelly,a,b,∗ Louise Vidal,b Tina McHugh,b James Woo,a Gordana Avramovic,b and John S. Lamberta,b
Abstract
Background
Up to 37.7% of patients experience symptoms beyond 12 weeks after infection with SARS-CoV-2. To date care for people with long covid has centred around multidisciplinary rehabilitation, self care and self pacing. No pharmacotherapy has been shown to be beneficial.
MethodsIn this single centre interventional pre post study, the safety of Low Dose Naltrexone (LDN) was explored in patients with Post COVID-19 Syndrome (PCS), defined by NICE as patients with ongoing symptoms 12 or more weeks after initial infections with SARS-CoV-2 where alternative explanation for symptoms cannot be found. Patients were recruited through a Post COVID clinic, had a baseline quality of life questionnaire in symmetrical Likert format, were prescribed 2 months (1 mg month one, 2 mg month two) of LDN and repeated the same questionnaire at the end of the second month. Patients were monitored to adverse events.
FindingsIn total 52 patients participated of whom 40(76.9%) were female. The median age was 43.5 years(IQR 33.2–49). Healthcare workers represented the largest occupational cohort n = 16(34.8%). The median time from diagnosis of COVID-19 until enrolment was 333 days (IQR 171–396.5). Thirty-eight participants (73.1%) were known to commence LDN, two of whom (5.3%) stopped taking LDN post commencement due to new onset diarrhoea and also described fatigue. In total 36(69.2%) participants completed the questionnaire at the end of the two-month period. Improvement was seen in 6 of 7 parameters measured; recovery from COVID-19, limitation in activities of daily living, energy levels, pain levels, levels of concentration and sleep disturbance (p ≤ 0.001), improvement in mood approached but was not significant (p = 0.054).
ConclusionsLDN is safe in patients with PCS and may improve well-being and reduce symptomatology in this cohort. Randomised control trials are needed to further explore this.
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Res Sq  . 2022 Jun 21;rs.3.rs-1716096.  doi: 10.21203/rs.3.rs-1716096/v1. Preprint
A pilot randomized controlled trial of supervised, at-home, self-administered transcutaneous auricular vagus nerve stimulation (taVNS) to manage long COVID symptomsBashar W Badran, Sarah M Huffman, Morgan Dancy, Christopher W Austelle, Marom Bikson, Steven A Kautz, Mark S George PMID: 35765566  PMCID: PMC9238186   
AbstractBackground Although the coronavirus disease 19 (COVID-19) pandemic has now impacted the world for over two years, the persistent secondary neuropsychiatric effects are still not fully understood. These "long COVID" symptoms, also referred to as post-acute sequelae of SARS-CoV-2 infection (PASC), can persist for months after infection without any effective treatments. Long COVID involves a complex heterogenous symptomology and can lead to disability and limit work. Long COVID symptoms may be due to sustained inflammatory responses and prolonged immune response after infection. Interestingly, vagus nerve stimulation (VNS) may have anti-inflammatory effects, however, until recently, VNS could not be self-administered, at-home, noninvasively. Methods We created a double-blind, noninvasive transcutaneous auricular VNS (taVNS) system that can be self-administered at home with simultaneous remote monitoring of physiological biomarkers and video supervision by study staff. Subsequently, we carried out a pilot (n = 13) randomized, sham-controlled, trial with this system for four weeks to treat nine predefined long covid symptoms (anxiety, depression, vertigo, anosmia, ageusia, headaches, fatigue, irritability, brain fog). No in-person patient contact was needed, with informed consent, trainings, ratings, and all procedures being conducted remotely during the pandemic (2020-2021) and equipment being shipped to individuals' homes. This trial was registered onClinicalTrials.gov under the identifier: NCT04638673. Results Four-weeks of at-home self-administered taVNS (two, one-hour sessions daily, delivered at suprathreshold intensities) was feasible and safe. Although our trial was not powered to determine efficacy as an intervention in a heterogenous population, the trends in the data suggest taVNS may have a mild to moderate effect in reducing mental fatigue symptoms in a subset of individuals. This innovative study demonstrates the safety and feasibility of supervised self-administered taVNS under a fully contactless protocol and suggests that future studies can safely investigate this novel form of brain stimulation at-home for a variety of neuropsychiatric and motor recovery applications.
 
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J Translational Medicine 2022 Jun 28;20(1):295.  doi: 10.1186/s12967-022-03488-3.
Oxaloacetate Treatment For Mental And Physical Fatigue In Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long-COVID fatigue patients: a non-randomized controlled clinical trialAlan Cash 1, David Lyons Kaufman 2 PMID: 35764955  PMCID: PMC9238249
AbstractBackground: There is no approved pharmaceutical intervention for Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS). Fatigue in these patients can last for decades. Long COVID may continue to ME/CFS, and currently, it is estimated that up to 20 million Americans have significant symptoms after COVID, and the most common symptom is fatigue. Anhydrous Enol-Oxaloacetate, (AEO) a nutritional supplement, has been anecdotally reported to relieve physical and mental fatigue and is dimished in ME/CFS patients. Here, we examine the use of higher dosage AEO as a medical food to relieve pathological fatigue.
Methods: ME/CFS and Long-COVID patients were enrolled in an open label dose escalating "Proof of Concept" non-randomized controlled clinical trial with 500 mg AEO capsules. Control was provided by a historical ME/CFS fatigue trial and supporting meta-analysis study, which showed average improvement with oral placebo using the Chalder Scale of 5.9% improvement from baseline. At baseline, 73.7% of the ME/CFS patients were women, average age was 47 and length of ME/CFS from diagnosis was 8.9 years. The Long-COVID patients were a random group that responded to social media advertising (Face Book) with symptoms for at least 6 months. ME/CFS patients were given separate doses of 500 mg BID (N = 23), 1,000 mg BID (N = 29) and 1000 mg TID (N = 24) AEO for six weeks. Long COVID patients were given 500 mg AEO BID (N = 22) and 1000 mg AEO (N = 21), again over a six-week period. The main outcome measure was to compare baseline scoring with results at 6 weeks with the Chalder Fatigue Score (Likert Scoring) versus historical placebo. The hypothesis being tested was formulated prior to data collection.
Results: 76 ME/CFS patients (73.7% women, median age of 47) showed an average reduction in fatigue at 6 weeks as measured by the "Chalder Fatigue Questionnaire" of 22.5% to 27.9% from baseline (P < 0.005) (Likert scoring). Both physical and mental fatigue were significantly improved over baseline and historical placebo. Fatigue amelioration in ME/CFS patients increased in a dose dependent manner from 21.7% for 500 mg BID to 27.6% for 1000 mg Oxaloacetate BID to 33.3% for 1000 mg TID. Long COVID patients' fatigue was significantly reduced by up to 46.8% in 6-weeks.
Conclusions: Significant reductions in physical and metal fatigue for ME/CFS and Long-COVID patients were seen after 6 weeks of treatment. As there has been little progress in providing fatigue relief for the millions of ME/CFS and Long COVID patients, anhydrous enol oxaloacetate may bridge this important medical need. Further study of oxaloacetate supplementation for the treatment of ME/CFS and Long COVID is warranted. 

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Biochem J   . 2022 Aug 31;479(16):1653-1708. doi: 10.1042/BCJ20220154.
The potential role of ischaemia-reperfusion injury in chronic, relapsing diseases such as rheumatoid arthritis, Long COVID, and ME/CFS: evidence, mechanisms, and therapeutic implicationsDouglas B Kell 1 2 3, Etheresia Pretorius PMID: 36043493Abstract
Ischaemia-reperfusion (I-R) injury, initiated via bursts of reactive oxygen species produced during the reoxygenation phase following hypoxia, is well known in a variety of acute circumstances. We argue here that I-R injury also underpins elements of the pathology of a variety of chronic, inflammatory diseases, including rheumatoid arthritis, ME/CFS and, our chief focus and most proximally, Long COVID. Ischaemia may be initiated via fibrin amyloid microclot blockage of capillaries, for instance as exercise is started; reperfusion is a necessary corollary when it finishes. We rehearse the mechanistic evidence for these occurrences here, in terms of their manifestation as oxidative stress, hyperinflammation, mast cell activation, the production of marker metabolites and related activities. Such microclot-based phenomena can explain both the breathlessness/fatigue and the post-exertional malaise that may be observed in these conditions, as well as many other observables. The recognition of these processes implies, mechanistically, that therapeutic benefit is potentially to be had from antioxidants, from anti-inflammatories, from iron chelators, and via suitable, safe fibrinolytics, and/or anti-clotting agents. We review the considerable existing evidence that is consistent with this, and with the biochemical mechanisms involved.

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Associations of Depression, Anxiety, Worry, Perceived Stress, and Loneliness Prior to Infection With Risk of Post–COVID-19 ConditionsSiwen Wang, MD1; Luwei Quan, BA2; Jorge E. Chavarro, ScD1,3,4; et alNatalie Slopen, ScD5; Laura D. Kubzansky, PhD5; Karestan C. Koenen, PhD3,5,6; Jae Hee Kang, ScD4; Marc G. Weisskopf, PhD2; Westyn Branch-Elliman, MD7,8; Andrea L. Roberts, PhD2
JAMA Psychiatry. Published online September 7, 2022. doi:10.1001/jamapsychiatry.2022.2640
Key Points
Question  Is psychological distress before SARS-CoV-2 infection associated with risk of COVID-19–related symptoms lasting 4 weeks or longer, known as post–COVID-19 conditions?
Findings  This cohort study found that among participants who did not report SARS-CoV-2 infection at baseline (April 2020) and reported a positive SARS-CoV-2 test result over 1 year of follow-up (N = 3193), depression, anxiety, perceived stress, loneliness, and worry about COVID-19 were prospectively associated with a 1.3- to 1.5-fold increased risk of self-reported post–COVID-19 conditions, as well as increased risk of daily life impairment related to post–COVID-19 conditions.
Meaning  In this study, preinfection psychological distress was associated with risk of post–COVID-19 conditions and daily life impairment in those with post–COVID-19 conditions.
Abstract
Importance  Few risk factors for long-lasting (≥4 weeks) COVID-19 symptoms have been identified.
Objective  To determine whether high levels of psychological distress before SARS-CoV-2 infection, characterized by depression, anxiety, worry, perceived stress, and loneliness, are prospectively associated with increased risk of developing post–COVID-19 conditions (sometimes called long COVID).
Design, Setting, and Participants  This prospective cohort study used data from 3 large ongoing, predominantly female cohorts: Nurses’ Health Study II, Nurses’ Health Study 3, and the Growing Up Today Study. Between April 2020 and November 2021, participants were followed up with periodic surveys. Participants were included if they reported no current or prior SARS-CoV-2 infection at the April 2020 baseline survey when distress was assessed and returned 1 or more follow-up questionnaires.
Exposures  Depression, anxiety, worry about COVID-19, perceived stress, and loneliness were measured at study baseline early in the pandemic, before SARS-CoV-2 infection, using validated questionnaires.
Main Outcomes and Measures  SARS-CoV-2 infection was self-reported during each of 6 monthly and then quarterly follow-up questionnaires. COVID-19–related symptoms lasting 4 weeks or longer and daily life impairment due to these symptoms were self-reported on the final questionnaire, 1 year after baseline.
Results  Of 54 960 participants, 38.0% (n = 20 902) were active health care workers, and 96.6% (n = 53 107) were female; the mean (SD) age was 57.5 (13.8) years. Six percent (3193 participants) reported a positive SARS-CoV-2 test result during follow-up (1-47 weeks after baseline). Among these, probable depression (risk ratio [RR], 1.32; 95% CI = 1.12-1.55), probable anxiety (RR = 1.42; 95% CI, 1.23-1.65), worry about COVID-19 (RR, 1.37; 95% CI, 1.17-1.61), perceived stress (highest vs lowest quartile: RR, 1.46; 95% CI, 1.18-1.81), and loneliness (RR, 1.32; 95% CI, 1.08-1.61) were each associated with post–COVID-19 conditions (1403 cases) in generalized estimating equation models adjusted for sociodemographic factors, health behaviors, and comorbidities. Participants with 2 or more types of distress prior to infection were at nearly 50% increased risk for post–COVID-19 conditions (RR, 1.49; 95% CI, 1.23-1.80). All types of distress were associated with increased risk of daily life impairment (783 cases) among individuals with post–COVID-19 conditions (RR range, 1.15-1.51).
Conclusions and Relevance  The findings of this study suggest that preinfection psychological distress may be a risk factor for post–COVID-19 conditions in individuals with SARS-CoV-2 infection. Future work should examine the biobehavioral mechanism linking psychological distress with persistent postinfection symptoms.

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Mol Cell Neurosci  . 2022 May;120:103731.  doi: 10.1016/j.mcn.2022.103731. Epub 2022 Apr 26.
Elevated ATG13 in serum of patients with ME/CFS stimulates oxidative stress response in microglial cells via activation of receptor for advanced glycation end products (RAGE)Gunnar Gottschalk 1, Daniel Peterson 2, Konstance Knox 3, Marco Maynard 4, Ryan J Whelan 4, Avik Roy 5     PMID: 35487443
Abstract
Myalgic Encephalomyelitis, also known as Chronic Fatigue Syndrome (ME/CFS), is a multisystem illness characterized by extreme muscle fatigue associated with pain, neurocognitive impairment, and chronic inflammation. Despite intense investigation, the molecular mechanism of this disease is still unknown. Here we demonstrate that autophagy-related protein ATG13 is strongly upregulated in the serum of ME/CFS patients, indicative of impairment in the metabolic events of autophagy. A Thioflavin T-based protein aggregation assay, array screening for autophagy-related factors, densitometric analyses, and confirmation with ELISA revealed that the level of ATG13 was strongly elevated in serum samples of ME/CFS patients compared to age-matched controls. Moreover, our microglia-based oxidative stress response experiments indicated that serum samples of ME/CFS patients evoke the production of reactive oxygen species (ROS) and nitric oxide in human HMC3 microglial cells, whereas neutralization of ATG13 strongly diminishes the production of ROS and NO, suggesting that ATG13 plays a role in the observed stress response in microglial cells. Finally, an in vitro ligand binding assay provided evidence that ATG13 employs the Receptor for Advanced Glycation End-products (RAGE) to stimulate ROS in microglial cells. Collectively, our results suggest that an impairment of autophagy following the release of ATG13 into serum could be a pathological signal in ME/CFS.
Keywords: ATG13; Autophagy; ME/CFS; Microglia: RAGE; NO; ROS.

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2022 Jun 23;9:917019.  doi: 10.3389/fmed.2022.917019. eCollection 2022.
Orthostatic Challenge Causes Distinctive Symptomatic, Hemodynamic and Cognitive Responses in Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue SyndromeSuzanne D Vernon 1, Sherlyn Funk 2, Lucinda Bateman 1, Gregory J Stoddard 2, Sarah Hammer 1, Karen Sullivan 1, Jennifer Bell 1, Saeed Abbaszadeh 1, W Ian Lipkin 3, Anthony L Komaroff 4
PMID: 35847821  PMCID: PMC9285104
AbstractBackground: Some patients with acute COVID-19 are left with persistent, debilitating fatigue, cognitive impairment ("brain fog"), orthostatic intolerance (OI) and other symptoms ("Long COVID"). Many of the symptoms are like those of other post-infectious fatigue syndromes and may meet criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Common diagnostic laboratory tests are often unrevealing.
Methods: We evaluated whether a simple, standardized, office-based test of OI, the 10-min NASA Lean Test (NLT), would aggravate symptoms and produce objective hemodynamic and cognitive abnormalities, the latter being evaluated by a simple smart phone-based app.
Participants: People with Long COVID (N = 42), ME/CFS (N = 26) and healthy control subjects (N = 20) were studied just before, during, immediately after, 2 and 7 days following completion of the NLT.
Results: The NLT provoked a worsening of symptoms in the two patient groups but not in healthy control subjects, and the severity of all symptoms was similar and significantly worse in the two patient groups than in the control subjects (p < 0.001). In the two patient groups, particularly those with Long COVID, the NLT provoked a marked and progressive narrowing in the pulse pressure. All three cognitive measures of reaction time worsened in the two patient groups immediately following the NLT, compared to the healthy control subjects, particularly in the Procedural Reaction Time (p < 0.01).
Conclusions: A test of orthostatic stress easily performed in an office setting reveals different symptomatic, hemodynamic and cognitive abnormalities in people with Long COVID and ME/CFS, compared to healthy control subjects. Thus, an orthostatic challenge easily performed in an office setting, and the use of a smart phone app to assess cognition, can provide objective confirmation of the orthostatic intolerance and brain fog reported by patients with Long COVID and ME/CFS.

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Vasc Health Risk Manag  . 2022 Sep 6;18:711-719.  doi: 10.2147/VHRM.S371468. eCollection 2022.
Chronic Fatigue Associated with Post-COVID Syndrome versus Transient Fatigue Caused by High-Intensity Exercise: Are They Comparable in Terms of Vascular Effects?Michal Chudzik 1 2, Anna Cender 1, Robert Mordaka 1, Jacek Zielinski 3, Joanna Katarzynska 4, Andrzej Marcinek 4 5, Jerzy Gebicki 4 5
PMID: 36097586  PMCID: PMC9464031
Abstract
Purpose: The pathophysiology of chronic fatigue associated with post-COVID syndrome is not well recognized. It is assumed that this condition is partly due to vascular dysfunction developed during an acute phase of infection. There is great demand for a diagnostic tool that is able to clinically assess post-COVID syndrome and monitor the rehabilitation process.
Patients and methods: The Flow Mediated Skin Fluorescence (FMSF) technique appears uniquely suitable for the analysis of basal microcirculatory oscillations and reactive hyperemia induced by transient ischemia. The FMSF was used to measure vascular circulation in 45 patients with post-COVID syndrome. The results were compared with those for a group of 26 amateur runners before and after high-intensity exercise as well as for a control group of 32 healthy age-matched individuals.
Results: Based on the observed changes in the NOI (Normoxia Oscillatory Index) and RHR (Reactive Hyperemia Response) parameters measured with the FMSF technique, it was found that chronic fatigue associated with post-COVID syndrome is comparable with transient fatigue caused by high-intensity exercise in terms of vascular effects, which are associated with vascular stress in the macrocirculation and microcirculation. Acute and chronic fatigue symptomatology shared similarly altered changes in the NOI and RHR parameters and both can be linked to calcium homeostasis modification.
Conclusion: The NOI and RHR parameters measured with the FMSF technique can be used for non-invasive clinical assessment of post-COVID syndrome as well as for monitoring the rehabilitation process.

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Biochem J. 2022 Aug 31;479(16):1653-1708.   doi: 10.1042/BCJ20220154.
The potential role of ischaemia-reperfusion injury in chronic, relapsing diseases such as rheumatoid arthritis, Long COVID, and ME/CFS: evidence, mechanisms, and therapeutic implicationsDouglas B Kell 1 2 3, Etheresia Pretorius 1 3PMID: 36043493  PMCID: PMC9484810
Abstract
Ischaemia-reperfusion (I-R) injury, initiated via bursts of reactive oxygen species produced during the reoxygenation phase following hypoxia, is well known in a variety of acute circumstances. We argue here that I-R injury also underpins elements of the pathology of a variety of chronic, inflammatory diseases, including rheumatoid arthritis, ME/CFS and, our chief focus and most proximally, Long COVID. Ischaemia may be initiated via fibrin amyloid microclot blockage of capillaries, for instance as exercise is started; reperfusion is a necessary corollary when it finishes. We rehearse the mechanistic evidence for these occurrences here, in terms of their manifestation as oxidative stress, hyperinflammation, mast cell activation, the production of marker metabolites and related activities. Such microclot-based phenomena can explain both the breathlessness/fatigue and the post-exertional malaise that may be observed in these conditions, as well as many other observables. The recognition of these processes implies, mechanistically, that therapeutic benefit is potentially to be had from antioxidants, from anti-inflammatories, from iron chelators, and via suitable, safe fibrinolytics, and/or anti-clotting agents. We review the considerable existing evidence that is consistent with this, and with the biochemical mechanisms involved.

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Comparison of the Degree of Deconditioning in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Patients with and without Orthostatic Intolerance – (Linda) M.C. van Campen, MD; Frans C. Visser, MD24 september 2022
ABSTRACT    Background
Orthostatic intolerance (OI) is a core finding in individuals with myalgic encephalomyelitis /chronic fatigue syndrome (ME/CFS).
Deconditioning is often proposed as an important determinant for OI. Deconditioning can be objectively classified using the predicted peak oxygen consumption (%VO2 peak) values as derived from cardiopulmonary exercise testing (CPET) and OI can be objectively quantified using cerebral blood flow (CBF) changes during tilt testing.
Therefore, if deconditioning contributes to OI, a correlation between peak VO2 and the %CBF reduction is expected.
 
Methods and results
18 healthy controls (HC) and 122 ME/CFS patients without hypotension or tachycardia on tilt- testing were studied. Deconditioning was classified as follows: %VO2 peak ≥85%= no deconditioning, %VO2 peak 65-85%= mild deconditioning, %VO2 peak<65%= severe deconditioning.
HC had higher %VO2 peak compared to ME/CFS patients (p<0.0001). ME/CFS patients had significantly larger CBF reduction than HC (p<0.0001).
No relation between the degree of deconditioning by the %VO2 peak and the %CBF reduction in ME/CFS patients was found. Moreover, we separately analyzed ME/CFS patients without an abnormal CBF reduction. Despite equal CBF reductions compared to HC and large differences between these patients and the patients with an abnormal CBF reduction, cardiac index (CI) changes (measured by suprasternal Doppler) were significantly less compared to ME/CFS patients with an abnormal CBF reduction (p<0.0001) but larger than in HC (p=0.004).
Despite these different hemodynamic findings, %VO2 values were not different between the two patient groups, argumenting again against the causative role of hemodynamic abnormalities in deconditioning. 
Conclusion
In ME/CFS patients without hypotension or tachycardia there is no relation between the %VO2 peak during CPET and the %CBF and %CI reduction during tilt testing, whether or not patients have an abnormal CBF reduction during tilt testing. It suggests again that deconditioning does not play an important role in OI.
Source: ESMED, June 20, 2022

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Pre-illness data reveals differences in multiple metabolites and metabolic pathways in those who do and do not recover from infectious mononucleosis 
Abstract:      Metabolic pathways related to energy production, amino acids, nucleotides, nitrogen, lipids, and neurotransmitters in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may contribute to the pathophysiology of ME/CFS.
Methods: 4501 Northwestern University college students were enrolled in a prospective, longitudinal study. We collected data before illness, during infectious mononucleosis (IM), and at a 6 month follow-up for those who recovered (N = 18) versus those who went on to develop ME/CFS 6 months later (N = 18).
Outcomes:  Examining pre-illness blood samples, we found significant detectable metabolite differences between participants fated to develop severe ME/CFS following IM versus recovered controls. We identified glutathione metabolism, nucleotide metabolism, and the TCA cycle (among others) as potentially dysregulated pathways.
The pathways that differed between cases and controls are essential for proliferating cells, particularly during a pro-inflammatory immune response.
Performing a series of binary logistic regressions using a leave-one-out cross-validation (LOOCV), our models correctly classified the severe ME/CFS group and recovered controls with an accuracy of 97.2%, sensitivity of 94.4%, and specificity of 100.0%.
Conclusion:  These changes are consistent with the elevations in pro-inflammatory cytokines that we have reported for patients fated to develop severe ME/CFS 6 months after IM.
Jason, Conroy, Furst, Vasan & Katz  - Source: Molecular Omics

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Pathophysiology of exercise intolerance in ME/CFS & long COVID – 
David Systrom, MD, Harvard Medical: Dr David Systrom’s keynote talk at the IACFS/ME Conference covered several different topics which were all related to acute exercise intolerance: preload failure, small nerve fibre neuropathy, skeletal muscle mitochondrial dysfunction, Long Covid and potential treatment.  Data presented was a mixture of published and unpublished studies. 
The basis of Dr Systrom’s research and work is based on using invasive cardiopulmonary exercise testing which was first used in heart and lung disease, however, not all patients were seen to fit this diagnosis, and led him to investigate ME/CFS. These patients were seen to have “preload failure”– where a consistently reduced max oxygen consumption (VO2) alongside reduced right atrial pressure (RAP), this means that there is poor oxygen extraction. It is this preload failure that contributes to post-exertional malaise (PEM). 
Dr Systrom’s research has also looked into small Nerve Fibre Neuropathy, which has been found in a subset (around 50% of patients), and he expects this might be related to exercise intolerance in ME/CFS. Similar findings have also been seen in POTS and fibromyalgia. As part of this branch of research, the immune response “TRAIL” which is a cytokine that is produced and secreted by most normal tissue cells, responsible for apoptosis (the death of cells). 
Another part of Dr Systrom’s talk also covered impaired oxygen extraction, which may be causing the depression in VO2 max. For this part of the research muscle biopsies were examined which suggests this might be linked to muscle mitochondrial dysfunction. 
Dr Systrom has also investigated exercise intolerance in Long Covid, which appears to be the same as ME/CFS with preload failure presence. Ventilatory inefficiency (VE/VCO2) is also present in Long Covid, which is due to hyperventilation (seen in a subset of patients). These findings are thought to be related to dyspnea. Furthermore, using upright tilt table testing for POTS and Long Covid patients verus controls has shown hyperventilation similar to that when performing exercise with depression of cerebral blood flow. 
Dr Systrom presented some unpublished data for ME/CFS, POTS and small Nerve Fibre Neuropathy showing that preload failure is present in all. 
Finally, the talk was concluded by a small introduction to treatment, using a small dose of pyridostigmine to treat preload failure. Results currently suggest in a subset of patients this treatment may be useful. 
Source: ME Association

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Phenotypic characteristics of peripheral immune cells of Myalgic encephalomyelitis/chronic fatigue syndrome via transmission electron microscopy: A pilot study:    AbstractPrevious studies have shown ME/CFS-associated alterations in the immune system and mitochondria. We used transmission electron microscopy (TEM) to investigate the morphology and ultrastructure of unstimulated and stimulated ME/CFS immune cells and their intracellular organelles, including mitochondria.
Method:   PBMCs from four participants were studied: a pair of identical twins discordant for moderate ME/CFS, as well as two age- and gender- matched unrelated subjects-one with an extremely severe form of ME/CFS and the other healthy.
Outcomes: TEM analysis of CD3/CD28-stimulated T cells suggested a significant increase in the levels of apoptotic and necrotic cell death in T cells from ME/CFS patients (over 2-fold).
Stimulated T-cells of ME/CFS patients also had higher numbers of swollen mitochondria.
We also found a large increase in intracellular giant lipid droplet-like organelles in the stimulated PBMCs from the extremely severe ME/CFS patient potentially indicative of a lipid storage disorder.
Lastly, we observed a slight increase in platelet aggregation in stimulated cells, suggestive of a possible role of platelet activity in ME/CFS pathophysiology and disease severity.
Conclusion:  These results indicate extensive morphological alterations in the cellular and mitochondrial phenotypes of ME/CFS patients’ immune cells and suggest new insights into ME/CFS biology.
Fereshteh Jahanbani, Rajan D Maynard, Justin Cyril Sing, Shaghayegh Jahanbani, John J Perrino, Damek V Spacek, Ronald W Davis, Michael P Snyder
Source: PubMed, Aug. 9, 2022

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Clinical Characteristics of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Diagnosed in Patients with Long COVIDAbstract:  Background and Objectives
COVID-19 can be serious not only in the acute phase but also after the acute phase and some patients develop ME/CFS.
There have been few studies on patients with long COVID in whom ME/CFS was diagnosed by physicians based on standardized criteria after examinations and exclusion diagnosis and not based on only subjective symptoms. The purpose of this study was to elucidate the detailed characteristics of ME/CFS in patients with long COVID.
Materials and Methods: A retrospective descriptive study was performed for patients who visited a COVID-19 aftercare clinic established in Okayama University Hospital during the period from February 2021 to April 2022.
Results:  Clinical data were obtained from medical records for 281 patients, and 279 patients who met the definition of long COVID were included. The overall prevalence rate of ME/CFS diagnosed by three sets of ME/CFS criteria (Fukuda, Canadian and IOM criteria) was 16.8% (48.9% in male and 51.1% in females).
The most frequent symptoms in ME/CFS patients were general fatigue and post-exertional malaise (89.4% of the patients), headache (34.0%), insomnia (23.4%), dysosmia (21.3%) and dysgeusia (19.1%). Dizziness, chest pain, insomnia and headache were characteristic symptoms related to ME/CFS.
The male to female ratio in ME/CFS patients was equal in the present study, although ME/CFS was generally more common in women in previous studies.
Given that patients with ME/CFS had more severe conditions in the acute phase of COVID-19, the severity of the acute infectious state might be involved in the pathophysiology of ME/CFS.
Conclusions: The prevalence rate of ME/CFS and the characteristic sequelae in the long COVID condition were revealed in this study.
Tokumasu, Honda, Sunda, Sakurada, Matsuda, Yamamoto, Nakano, Hasegawi, Yamamoto, Otsuka, Hagiya, Kataoka, Ueda & Otsuka

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Inflammations in the brain in ME – Prof. Jarred YoungerWe have heard little from Prof Jarred Younger for a long time. Perhaps there was even a fear that he was no longer engaged in ME research. Fortunately, nothing could be further from the truth, as evidenced by a recent webinar facilitated by Solve ME.
In it, he explains not only what he has been doing over the past few years, but also the promising progress he has made. Central to this remains the demonstration of (low-grade) inflammations in the brain in ME.
Demonstrating inflammations in the brain - To do so, he uses three angles:
1. Temperature measurements
2. Tracking of leucocytes
3. Tracking of microglia
Its ultimate goal is to find treatments for ME.
In the video Prof. Younger gives a comprehensive account of those three techniques and the possible results. The focus is on microglia, the nerve cells in the brain. Virtually all symptoms in ME may result from low-grade, chronic inflammation of these.
Tracking leucocytes (T- & B-cells)
You can’t open the skull and then take out some cells to see if it contains Leukocytes that don’t belong there (and can do a lot of damage). He now adds Zircon89 and manages to make them visible with scans, because it takes three days for leukocytes to reach the brain (if they do). In 4 healthy, he found no leukocytes in the brain.
He is now going to apply that to 1 ME patient first. Exciting…   Should he find leukocytes in their brains, there will be a fast track to treatments. He hopes to announce the results in about three months’ time.
Tracking microglia
Done with a PET scan and an injected radioactive substance (DPA 714), which attaches itself to microglia that are inflamed. That technique is already being used. It has not yet been used in ME research mainly due to cost.
Conclusions
There is a lot going on, and he expects to announce much of it in the second half of 2022. He advises every patient to participate in research, if possible. Because patient participation (and also ongoing NGO funding of pilot studies) are the basis for achieving discoveries on a larger scale.
Source text and photo: https://youtu.be/DU0UgWGyi0A
Extract ME Global Chronicle

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Survey of Anti-Pathogen Antibody Levels in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Abstract
Infectious pathogens are implicated in the etiology of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) because of the occurrence of outbreaks of the disease.
While a number of different infectious agents have been associated with the onset of ME/CFS, the identity of a specific organism has been difficult to determine in individual cases.
Aim
The aim of our study is to survey ME/CFS subjects for evidence of an infectious trigger and/or evidence of immune dysregulation via serological testing of plasma samples for antibodies to 122 different pathogen antigens.
Method
Immune profiles were compared to age-, sex-, and BMI-matched controls to provide a basis for comparison.
Results
Antibody levels to individual antigens surveyed in this study do not implicate any one of the pathogens in ME/CFS, nor do they rule out common pathogens that frequently infect the US population.
However, our results revealed sex-based differences in steady-state humoral immunity, both within the ME/CFS cohort and when compared to trends seen in the healthy control cohort.
O’Neal, Glass, Emig, Vitug, Henry, Shungu, Mao, Levine & Hanson
Source: MDPI Proteomes

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Activity monitoring and patient-reported outcome measures in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients
Abstract:   Introduction:  Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disease with no validated specific and sensitive biomarker, and no standard approved treatment. In this observational study with no intervention, participants used a Fitbit activity tracker. The aims were to explore natural symptom variation, feasibility of continuous activity monitoring, and to compare activity data with patient reported outcome measures (PROMs).
Materials and methods:   In this pilot study, 27 patients with mild to severe ME/CFS, of mean age 42.3 years, used the Fitbit Charge 3 continuously for six months. Patients wore a SenseWear activity bracelet for 7 days at baseline, at 3 and 6 months. At baseline and follow-up they completed the Short Form 36 Health Survey (SF-36) and the DePaul Symptom Questionnaire-Short Form (DSQ-SF).
Results:  The mean number of steps per day decreased with increasing ME/CFS severity; mild 5566, moderate 4991 and severe 1998.
The day-by-day variation was mean 47% (range 25%-79%). Mean steps per day increased from the first to the second three-month period, 4341 vs 4781 steps. The maximum differences in outcome measures between 4-week periods (highest vs lowest), were more evident in a group of eight patients with milder disease (baseline SF-36 PF > 50 or DSQ-SF < 55) as compared to 19 patients with higher symptom burden (SF-36 PF < 50 and DSQ-SF > 55), for SF-36 PF raw scores: 16.9 vs 3.4 points, and for steps per day: 958 versus 479 steps.
The correlations between steps per day and self-reported SF-36 Physical function, SF-36 Social function, and DSQ-SF were significant. Fitbit recorded significantly higher number of steps than SenseWear. Resting heart rates were stable during six months.
Conclusion:  Continuous activity registration with Fitbit Charge 3 trackers is feasible and useful in studies with ME/CFS patients to monitor steps and resting heart rate, in addition to self-reported outcome measures.       Rekeland, Sørland, Bruland, Risa, Alme, Dahl, Tronstad, Mella & Fluge
Source: PLOS ONE 

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Brain, Behavior, and Immunity       Volume 102, May 2022, Pages 362-369
 
Genetic association study in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) identifies several potential risk lociRiadHajdarevicabAsgeirLandeaJesperMehlsencAnneRydlandabDaisy D.SosadeElin B.StrandfgOlavMellahFlemmingPociotiØysteinFlugehBenedicte A.LieabjMarte K.Vikenaj
Received 26 September 2021, Revised 3 March 2022, Accepted 16 March 2022, Available online 19 March 2022, Version of Record 23 March 2022.

Highlights
Largest ME/CFS genetic study to date.
Three different cohorts totaling >2500 patients.
First Immunochip study in ME/CFS.
Possible implication of TPPP genetic region.
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease of unknown etiology and pathogenesis, which manifests in a variety of symptoms like post-exertional malaise, brain fog, fatigue and pain. Hereditability is suggested by an increased disease risk in relatives, however, genome-wide association studies in ME/CFS have been limited by small sample sizes and broad diagnostic criteria, therefore no established risk loci exist to date. In this study, we have analyzed three ME/CFS cohorts: a Norwegian discovery cohort (N = 427), a Danish replication cohort (N = 460) and a replication dataset from the UK biobank (N = 2105). To the best of our knowledge, this is the first ME/CFS genome-wide association study of this magnitude incorporating 2532 patients for the genome-wide analyses and 460 patients for a targeted analysis. Even so, we did not find any ME/CFS risk loci displaying genome-wide significance. In the Norwegian discovery cohort, the TPPP gene region showed the most significant association (rs115523291, P = 8.5 × 10−7), but we could not replicate the top SNP. However, several other SNPs in the TPPP gene identified in the Norwegian discovery cohort showed modest association signals in the self-reported UK biobank CFS cohort, which was also present in the combined analysis of the Norwegian and UK biobank cohorts, TPPP (rs139264145; P = 0.00004). Interestingly, TPPP is expressed in brain tissues, hence it will be interesting to see whether this association, with time, will be verified in even larger cohorts. Taken together our study, despite being the largest to date, could not establish any ME/CFS risk loci, but comprises data for future studies to accumulate the power needed to reach genome-wide significance.

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Orji et al. BMC Public Health (2022) 22:1516 https://doi.org/10.1186/s12889-022-13929-9 
RESEARCH Prevalence of myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS) in Australian primary care patients: only part of the story?
Nneka Orji1 , Julie A. Campbell1 , Karen Wills1 , Martin Hensher1 , Andrew J. Palmer1 , Melissa Rogerson2 , Ryan Kelly2 and Barbara de Graaf1* 
Abstract/ Background: ME/CFS is a disorder characterized by recurrent fatigue and intolerance to exertion which manifests as profound post-exertional malaise. Prevalence studies internationally have reported highly variable results due to the 20+diagnostic criteria. For Australia, the prevalence of ME/CFS based on current case defnitions is unknown. 
Objectives: To report prevalence of ME/CFS in patients aged≥13 years attending Australian primary care settings for years 2015–2019, and provide context for patterns of primary care attendance by people living with ME/CFS. 
Methodology: Conducted in partnership with the Patient Advisory Group, this study adopted a mixed methods approach. De-identifed primary care data from the national MedicineInsight program were analyzed. The cohort were regularly attending patients, i.e. 3 visits in the preceding 2 years. Crude prevalence rates were calculated for years 2015–2019, by sex, 10-year age groups, remoteness and socioeconomic status. Rates are presented per 100,000population (95% confdence intervals (CI)). Qualitative data was collected through focus groups and in-depth 1:1 interview. 
Results: Qualitative evidence identifed barriers to reaching diagnosis, and limited interactions with primary care due to a lack of available treatments/interventions, stigma and disbelief in ME/CFS as a condition. In each year of interest, crude prevalence in the primary care setting ranged between 94.9/100,000 (95% CI: 91.5–98.5) and 103.9/100,000 population (95%CI: 100.3–107.7), equating to between 20,140 and 22,050 people living with ME/ CFS in Australia in 2020. Higher rates were observed for age groups 50-59 years and 40-49 years. Rates were substantially higher in females (130.0–141.4/100,000) compared to males (50.9–57.5/100,000). In the context of the qualitative evidence, our prevalence rates likely represent an underestimate of the true prevalence of ME/CFS in the Australian primary care setting. 
Conclusion: ME/CFS afects a substantial number of Australians. Whilst this study provides prevalence estimates for the Australian primary care setting, the qualitative evidence highlights the limitations of these. Future research should focus on using robust case ascertainment criteria in a community setting. Quantifcation of the burden of disease can be used to inform health policy and planning, for this understudied condition. Keywords: Chronic fatigue syndrome, Myalgic encephalomyelitis, ME/CFS, Prevalence, Primary care, Mixed method

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Understanding myalgic encephalomyelitis
Myalgic encephalomyelitis and Long Covid have overlapping presentation
SONYA MARSHALL-GRADISNIK AND NATALIE EATON-FITCH
SCIENCE 8 Sep 2022  Vol 377, Issue 6611  pp. 1150-1151  DOI: 10.1126/science.abo1261
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severe condition characterized by post-exertional neuroimmune exhaustion (PENE) accompanied by neurological, immunological, gastrointestinal (GI), and mitochondrial disturbances (1). The global prevalence of ME/CFS is ∼1%, affecting 17 million to 24 million people (2). ME/CFS is heterogeneous not only in symptom presentation but also illness trajectories, which can be worsening, plateauing, improving, or relapsing-remitting. Approximately 25% of patients with ME/CFS are considered severe and are bound to their homes. Although the etiology of ME/CFS is elusive, a large proportion of patients (∼60%) report post-infectious onset, such as after Epstein-Barr virus infection (3). The recent emergence of a chronic post-infectious condition, called Long Covid, overlaps considerably with ME/CFS in immunological, mitochondrial, and neurological dysfunctions (4). These similarities have resulted in increased interest and acceptance of ME/CFS as a disease and may stimulate research, the development of a diagnostic test, and pharmacotherapeutic interventions in ME/CFS that may be applied to Long Covid.
 
Neurological disturbances such as cognitive impairment, autonomic dysfunction, altered pain and sensory perception, and sleep disturbances are essential for diagnosis of ME/CFS and are commonly reported in Long Covid (see the figure). The World Health Organization (WHO) categorizes ME/CFS as a disease of the nervous system. Neuroimaging of ME/CFS patients has revealed anatomical, neurochemical, and functional brain changes. For example, brain magnetic resonance imaging (MRI) found global gray and white matter volume changes and also differences in the cortical and subcortical regional volumes in ME/CFS patients (5). Impaired brainstem connectivity identified with functional MRI (fMRI) and regression of white matter was associated with autonomic nervous system (ANS) measures in ME/CFS, including sleep disturbances and respiratory rate, which may lead to other symptoms, including pain, fatigue, impaired concentration and memory, and sensory and motor dysfunction (6). Such neurological symptoms are also commonly reported by Long Covid patients, and brain MRI has shown higher gray matter volumes in hippocampi that correlated with memory loss, a result also reported in ME/CFS (4). Overall, the underlying mechanism resulting in these MRI findings is unclear. Nonetheless, MRI and fMRI are important techniques to help elucidate the pathology of ME/CFS, as well as Long Covid.

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Autoimmun Rev  . 2016 Jun;15(6):552-7.  doi: 10.1016/j.autrev.2016.02.011. Epub 2016 Feb 12.
Autoantibody pain
Andreas Goebel 1
PMID: 26883460
Abstract
As autoantibodies bind to target tissues, Fc-region dependent inflammation can induce pain via mediators exciting nociceptors. But recently another possibility has emerged, where autoantibody binding to nociceptors can directly cause pain, without inflammation. This is thought to occur as a result of Fab-region mediated modification of nerve transduction, transmission, or neuropeptide release. In three conditions, complex regional pain syndrome, anti-voltage gated potassium channel complex autoimmunity, and chronic fatigue syndrome, all associated with no or only little inflammation, initial laboratory-, and clinical trial-results have suggested a potential role for autoantibody-mediated mechanisms. More research assessing the pathogenic roles of autoantibodies in these and other chronic pain conditions is required. The concept of autoantibody-mediated pain offers hope for the development of novel therapies for currently intractable pains.
Keywords: Autoantibody; CRPS; Chronic fatigue syndrome; Complex regional pain syndrome; Neuropathic pain; Pain; Voltage gated potassium channels.

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Autoimmunity Reviews Volume 21, Issue 3, March 2022, 103015The autoimmune aetiology of unexplained chronic painAuthor links open overlay panelAndreasGoebela1DavidAnderssonb1ZsuzsannaHelyesc1J. DavidClarkd1DebraDulakee1CamillaSvenssonf1
https://doi.org/10.1016/j.autrev.2021.103015Get rights and content
Abstract
Chronic pain is the leading cause of life years lived with disability worldwide. The aetiology of most chronic pain conditions has remained poorly understood and there is a dearth of effective therapies. The WHO ICD-11 has categorised unexplained chronic pain states as ‘chronic primary pains’ (CPP), which are further defined by their association with significant distress and/or dysfunction. The new mechanistic term, ‘nociplasticic pain’ has been developed to illustrate their presumed generation by a structurally intact, but abnormally functioning nociceptive system. Recently, researchers have unravelled the surprising, ubiquitous presence of pain-sensitising autoantibodies in four investigated CPP indicating autoimmune causation. In persistent complex regional pain syndrome, fibromyalgia syndrome, chronic post-traumatic limb pain, and non-inflammatory joint pain associated with rheumatoid arthritis, passive transfer experiments have shown that either IgG or IgM antibodies from patient-donors cause symptoms upon injection to rodents that closely resemble those of the clinical disorders. Targets of antibody-binding and downstream effects vary between conditions, and more research is needed to elucidate the molecular and cellular details. The central nervous system appears largely unaffected by antibody binding, suggesting that the clinically evident CNS symptoms associated with CPP might arise downstream of peripheral processes. In this narrative review pertinent findings are described, and it is suggested that additional symptom-based disorders might be examined for the contribution of antibody-mediated autoimmune mechanisms.

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Infectious Diseases  September 27, 2022
Association of SARS-CoV-2 Seropositivity With Myalgic Encephalomyelitis and/or Chronic Fatigue Syndrome Among Children and Adolescents in GermanyAnna-Lisa Sorg, MSc1,2; Selina Becht, MSc1; Marietta Jank, MD3; et alJakob Armann, MD4; Ulrich von Both, MD5; Markus Hufnagel, MD6; Fabian Lander, MD7; Johannes G. Liese, MD8; Tim Niehues, MD9; Eva Verjans, MD10; Martin Wetzke, MD11; Silvia Stojanov, MD12; Uta Behrends, MD12; Christian Drosten, MD13; Horst Schroten, MD3; Rüdiger von Kries, MD1
JAMA Netw Open. 2022;5(9):e2233454. doi:10.1001/jamanetworkopen.2022.33454
Key Points
Question  Is SARS-CoV-2 seropositivity associated with symptoms of myalgic encephalomyelitis and/or chronic fatigue syndrome (ME/CFS) in children and adolescents?
Findings  This cross-sectional study of hospital-based SARS-CoV-2 seroprevalence surveys in Germany compared seropositive and seronegative children and adolescents and identified an excess of possible ME/CFS symptoms with serological evidence of preceding SARS-CoV-2 infection. This association almost disappeared with adjustment for confounders and restriction to children and adolescents unaware of preceding infection.
Meaning  These findings suggest that the risk of ME/CFS after SARS-CoV-2 infection in children and adolescents may be small and that recall bias may contribute to risk estimates.
Abstract
Importance  During the COVID-19 pandemic, a reduction in quality of life and physical and mental health among children and adolescents has been reported that may be associated with SARS-CoV-2 infection and/or containment measures.
Objective  To assess the association of SARS-CoV-2 seropositivity with symptoms that may be related to myalgic encephalomyelitis and/or chronic fatigue syndrome (ME/CFS) among children and adolescents.
Design, Setting, and Participants  This substudy of the cross-sectional SARS-CoV-2 seroprevalence surveys in Germany (SARS-CoV-2 KIDS) was performed in 9 pediatric hospitals from May 1 to October 31, 2021. Pediatric patients were recruited during an inpatient or outpatient visit regardless of the purpose of the visit. Parental questionnaires and serum samples were collected during clinically indicated blood draws. The parental questionnaire on demographic and clinical information was extended by items according to the DePaul Symptom Questionnaire, a pediatric screening tool for ME/CFS in epidemiological studies in patients aged 5 to 17 years.
Exposures  Seropositivity was determined by SARS-CoV-2 IgG antibodies in serum samples using enzyme-linked immunosorbent assays.
Main Outcomes and Measures  Key symptoms of ME/CFS were evaluated separately or as clustered ME/CFS symptoms according to the DePaul Symptom Questionnaire, including fatigue.
Results  Among 634 participants (294 male [46.4%] and 340 female [53.6%]; median age, 11.5 [IQR, 8-14] years), 198 (31.2%) reported clustered ME/CFS symptoms, including 40 of 100 SARS-CoV-2–seropositive (40.0%) and 158 of 534 SARS-CoV-2–seronegative (29.6%) children and adolescents. After adjustment for sex, age group, and preexisting disease, the risk ratio for reporting clustered ME/CFS symptoms decreased from 1.35 (95% CI, 1.03-1.78) to 1.18 (95% CI, 0.90-1.53) and for substantial fatigue from 2.45 (95% CI, 1.24-4.84) to 2.08 (95% CI, 1.05-4.13). Confinement to children and adolescents with unknown previous SARS-CoV-2 infection status (n = 610) yielded lower adjusted risks for all symptoms except joint pain ME/CFS–related symptoms. The adjusted risk ratio was 1.08 (95% CI, 0.80-1.46) for reporting clustered ME/CFS symptoms and 1.43 (95% CI, 0.63-3.23) for fatigue.
Conclusions and Relevance  These findings suggest that the risk of ME/CFS in children and adolescents owing to SARS-CoV-2 infection may be very small. Recall bias may contribute to risk estimates of long COVID-19 symptoms in children. Extensive lockdowns must be considered as an alternative explanation for complex unspecific symptoms during the COVID-19 pandemic.